Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial.

UNLABELLED: Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5 years were consistent with those seen at 3 years. INTRODUCTION: We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis. METHODS: In the core study, healthy postmenopausal women with osteoporosis (N=7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40 mg were transitioned in a blinded manner to bazedoxifene 20 mg (bazedoxifene 40-/20-mg group) after 4 years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere. RESULTS: A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium. CONCLUSION: Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5 years of therapy, consistent with findings at 3 years.

Long-term treatment of postmenopausal osteoporosis with strontium ranelate: results at 8 years.

OBJECTIVES: Strontium ranelate 2 g/day has proven efficacy against vertebral and nonvertebral fracture over 5 years in postmenopausal osteoporosis, though many women require longer-term treatment. This article describes the efficacy, safety, and tolerability of this agent over 8 years. METHODS: Postmenopausal osteoporotic women having participated in the 5-year efficacy trials SOTI and TROPOS were invited to enter a 3-year open-label extension study. The results presented here focus on patients who received strontium ranelate for 8 years. RESULTS: At the extension baseline, the population treated for 8 years (n=879; 79.1+/-5.6 years) had femoral neck T-score of -2.61+/-0.71. The cumulative incidences of new vertebral and nonvertebral fractures (13.7% and 12.0%, respectively) over years 6 to 8 were non-statistically different from the cumulative incidences in the first 3 years of the original studies (11.5% and 9.6%). Lumbar spine, femoral neck, and total hip bone mineral density (BMD) increased throughout the 8-year period. Annual relative change in BMD was significant at every visit, except the 8-year visit for femoral neck and total hip BMD. Strontium ranelate was safe and well tolerated over 8 years. CONCLUSIONS: Long-term treatment with strontium ranelate 2 g/day in postmenopausal osteoporotic women leads to continued increases in BMD at all sites. The data also provide some evidence for a sustained antifracture efficacy.

Assessment of changes due to the long-term effect of estrogen and calcium deficiency in the trabecular bone structure in rats.

OBJECTIVE: To assess structural changes, especially structural anisotropy, of rat bone trabecular system 6 months after ovariectomy followed by low-calcium diet. METHOD: The study was carried out on the group of 32 female rats, half of which were ovariectomized at the age of 75 days. The animals were divided into 4 groups: one receiving a normal diet (N), another receiving a low-calcium diet (LCa), ovariectomized rats receiving a normal diet (OVX), and ovariectomized animals receiving a low-calcium diet (OVX+LCa). After 6 months the animals were killed, bone specimens were collected and cut into sections of 6 microm thickness. Digital images of the sections were analyzed using a software package enabling analysis of the transversal and longitudinal trabeculae. RESULTS: Significant changes in trabecular structure due to a low-calcium diet (trabecular bone volume loss of 19%), ovariectomy (53%) and ovariectomy combined with low-calcium diet (71%) were observed. In all the analyzed groups, the percentage loss (as compared with controls) of transversal trabeculae was more significant than the loss of longitudinal trabeculae. In the LCa group, transversal trabecular loss was 39%, longitudinal 25%, in (Ovx): 63% and 54%, respectively, and in OVX + LCa: 77% and 72%. The structural anisotropy coefficient, defined as the ratio of transversal to longitudinal trabecular surface area was 0.64 for (N), 0.50 for LCa, 0.49 for OVX, and 0.54 for OVX+LCa groups. CONCLUSIONS: The effect of ovariectomy and low-calcium diet on trabecular structure can be assessed quantitatively by means of analysis of transversal and longitudinal trabeculae associated with the main direction of strain. The degree of transversal trabecular loss is much higher than the longitudinal trabecular loss; the difference becomes smaller with the progress of bone destruction, being greatest in the LCa group, the smallest in the (OVX+ LCa) group.

Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study.

BACKGROUND: Strontium ranelate, a new oral drug shown to reduce vertebral fracture risk in postmenopausal women with osteoporosis, was studied in the Treatment of Peripheral Osteoporosis (TROPOS) study to assess its efficacy and safety in preventing nonvertebral fractures also. METHODS: Strontium ranelate (2 g/d) or placebo were randomly allocated to 5091 postmenopausal women with osteoporosis in a double-blind placebo-controlled 5-yr study with a main statistical analysis over 3 yr of treatment. FINDINGS: In the entire sample, relative risk (RR) was reduced by 16% for all nonvertebral fractures (P = 0.04), and by 19% for major fragility fractures (hip, wrist, pelvis and sacrum, ribs and sternum, clavicle, humerus) (P = 0.031) in strontium ranelate-treated patients in comparison with the placebo group. Among women at high risk of hip fracture (age > or = 74 yr and femoral neck bone mineral density T score < or = -3, corresponding to -2.4 according to NHANES reference) (n = 1977), the RR reduction for hip fracture was 36% (P = 0.046). RR of vertebral fractures was reduced by 39% (P < 0.001) in the 3640 patients with spinal x-rays and by 45% in the subgroup without prevalent vertebral fracture. Strontium ranelate increased bone mineral density throughout the study, reaching at 3 yr (P < 0.001): +8.2% (femoral neck) and +9.8% (total hip). Incidence of adverse events (AEs) was similar in both groups. CONCLUSION: This study shows that strontium ranelate significantly reduces the risk of all nonvertebral and in a high-risk subgroup, hip fractures over a 3-yr period, and is well tolerated. It confirms that strontium ranelate reduces vertebral fractures. Strontium ranelate offers a safe and effective means of reducing the risk of fracture associated with osteoporosis.

Assessment of trabecular bone structure in postmenopausal and senile osteoporosis in women by image analysis.

OBJECTIVE: The aim of the study was to assess bone trabecular structure in postmenopausal and senile osteoporosis. METHODS: The study was performed on transiliac specimens obtained from women with postmenopausal (n=10) and senile osteoporosis (n=10) and on normal autopsy bone (n=7). Digitalized microradiographs were analysed using dedicated software allowing for selection of longitudinal and transversal elements. RESULTS: Significant differences between transversal and control, as well as between longitudinal and control trabecular areas were observed in senile osteoporosis (p<0.005). In postmenopausal osteoporosis, such differences were found for longitudinal trabeculae only (p<0.005). Mean longitudinal trabecular area loss in senile and postmenopausal osteoporosis as compared to control group was 57.2% and 25.7%, respectively. Respective values for transversal trabecular area were 35.0% and 59.4%. CONCLUSION: Structural anisotropy of trabecular bone is greater in postmenopausal than in senile osteoporosis and control group. The method developed allows the evaluation of bone structures in radiographs with uneven exposure.

Peptic ulcer disease and calcium intake as risk factors of osteoporosis in women.

INTRODUCTION: Low dietary intake and decreased absorption of calcium are known as important risk factors of osteoporosis. Peptic ulcer disease may be accompanied by dietary restrictions influencing negatively calcium intake. Inflammation of gastric and duodenal mucosa as well as alkali used may significantly decrease calcium absorption. Additionally, bone metabolism may be changed by inflammatory mediators released as a result of mucosal inflammation. AIMS: Comparison of bone mineral density and calcium dietary intake in women with and without (control group) peptic ulcer disease. METHODS: Two hundred and sixty-three women were studied: 143 (mean age 60.3 years) with peptic ulcer disease diagnosed by endoscopy and/or upper gastrointestinal X-ray, and 120 (mean age 58.4 years) as controls. History of alimentary tract diseases and presence of risk factors of osteoporosis, as well as history of hormone replacement therapy, were collected based on specially designed questionnaires. Women with present risk factors of secondary osteoporosis and with previously diagnosed osteoporosis were excluded. The calcium dietary intake was determined using a standard questionnaire assessing milk and milk products intake as well as calcium supplementation when used. Bone mineral density of the lumbar spine and femoral bone was determined by DXA. RESULTS: Women with peptic ulcer disease not using hormone replacement therapy had lower bone mineral density in all studied regions as compared to control group without peptic ulcer disease. In the subgroup not using hormone replacement therapy all studied values differed significantly. In the smaller subgroup of women using hormone replacement therapy not all values were statistically significant. There was no statistical significance between studied groups in dietary calcium intake as milk, milk products, and calcium supplements. CONCLUSIONS: Calcium intake in women with ulcer disease is similar to healthy subjects. Peptic ulcer disease is an independent risk factor for osteoporosis in women.

Imaging of bone in the diagnostics of renal osteodystrophy in children with chronic renal failure.

BACKGROUND: In the last two decades considerable advances have been made in the development of imaging tests of the skeletal system. This progress in diagnostic techniques, along with the growing availability of the tests, renders it necessary to review and evaluate their suitability for daily clinical practice. The aim of this article is to compare the results of radiological testing of bone with densitometrical, histomorphometric, and biochemical tests in children with chronic renal failure. MATERIAL AND METHODS: The research involved 31 children with renal failure, of whom 10 were being treated conservatively, 17 by continuous ambulatory peritoneal dialysis (CADO), and 4 by hemodialysis (HD). In all these children, radiological examinations of bone were performed in the arms, knees, and hips, along with tests for the serum concentration of parathormone (iPTH), calcium (Ca), and phosphates (P), and for the activity of alkaline phosphatase (AP). Bone density tests by the DXA method and bone biopsies were also performed. On the basis of radiological evaluation, the patients were divided into two groups: Group I, consisting of 14 children with a normal bone structure image, and Group II, consisting of 17 children with bone atrophy. RESULTS: No statistically significant differences were discovered in the mean values of the tested biochemical parameters between the two groups. The mineral density of total body was normal in 9 of the 14 patients in Group I (64%), and in 7 of 17 (41%) from Group II. The mineral density of total lumbar spine gave similar results. Lower bone density results were obtained in Group II than in Group I, though only in the case of the lumbar spine were the differences statistically significant. In Group I, 5 cases were discovered of chronic osteodystrophy without osteomalacia and hyperparathyroidism (NB), 2 cases of adynamic bone disease (ABD), 4 cases of hyperparathyroidism (HP), 2 cases of moderate hyperparathyroidism (MHP), and one mixed form (Mix); in Group II, there were 6 NBs, 2 ABDs, 1 case of osteomalacia (OM), 5 HPs, and 3 mixed. Radiological examinations revealed one male in Group I with features of prior Perthes's disease, one with fibrous cortical defect, and four cases of valgity of the coxa valga. In Group II, there were 3 children with radiological changes typical for osteomalacia, and in 1 case typical radiological signs of hyperparathyroidism. CONCLUSIONS: Given the lack of consistency in the results of the tests here presented, an entire panel of available tests should be performed for the comprehensive evaluation of the status of the skeleton.

[Risk factors of adynamic bone disease in children with end-stage renal failure: personal experience]. / Czynniki ryzyka adynamicznej choroby kosci u dzieci ze schylkowa niewydolnoscia nerek--doswiadczenia wlasne.

The aim of the study was to estimate predisposing factors which can cause adynamic bone disease (ABD) and biochemical markers, bone densitometry results, bone histomorphometry in 17 children with this from of the renal osteodystrophy. Half of these of patients were treated with alphacalcidol pulses. In 47% of patients hypercalcemic episodes were noted, 76% had PTH level < 50 pg/ml. Four patients with osteoporosis (low bone volume at histological analysis) were distinguished. Two of them were treated with corticosteroids, 1 was immobilized for a long time.

[Bone metabolism markers and bone histomorphometry in children with chronic renal failure in predialysis period during growth hormone treatment]. / Markery metabolizmu kostnego u dzieci z przewlekla niewydolnoscia nerek leczonych hormonem wzrostu w okresie przeddializacyjnym.

The aim of the study was to estimate biochemical bone metabolism markers and bone histomorphometric parameters in children with chronic renal failure (CRF) treated with recombinant human growth hormone (rhGH). Twelve children with CRF aged 2-13.4 years were treated with rhGH 1-1.1 IU/kg per week and alfacalcidol. Bone biopsies were performed before and after 12 months of therapy. An increase in the biochemical markers of bone formation and bone resorption were noted. A statistically significant increase in mineral apposition rate (MAR) was observed in bone histomorphometry. The administration of active vitamin D metabolites enable proper bone mineralization in fast growing children with CRF during rhGH treatment.

Bone biopsy results and serum bone turnover parameters in uremic children.

UNLABELLED: The aim of the study was to evaluate the prevalence of renal osteodystrophy types in children undergoing haemodialysis and continuous ambulatory peritoneal dialysis and to assess the usefulness of biochemical parameters in diagnosis of renal osteodystrophy. Bone biopsy and measurements of serum parathormone (iPTH) level, alkaline phosphatase (AP), osteocalcin (OC), procollagen 1C, calcium and phosphorus levels were performed in 51 children aged 11.5 +/- 2.9 y with end-stage renal failure. Renal osteodystrophy (ROD) was diagnosed as follows: adynamic bone disease (ABD) in 14 (27%); normal bone histology (NB) in 19 (37%), osteomalacia (OM) in 1 (2%), mixed lesion (Mix) in 5 (10%) and hyperparathyroidism (HP) in 12 (24%) children. There was no difference in prevalence of ROD types between children on CAPD and HD. We found significant differences in the mean value of iPTH, OC levels and AP activity in HP vs NB and HP vs ABD. The prevalence of ABD was significantly higher in patients with PTH below 50 pg/ml than in patients with PTH above 50 pg/ml (p < 0.05). In 69% of children with NB the iPTH level was between 50 and 150 pg/ml. Most HP cases (75%) were diagnosed in patients with iPTH above 200 pg/ml. A high correlation between BFR and iPTH, BFR and OC, AP levels was found. CONCLUSION: The biochemical markers of bone turnover have only limited value in the differentiation of renal osteodystrophy types.

Detection of bone disease with ultrasound--comparison with bone densitometry.

A system for ultrasonic in-vivo examination of a heel bone (calcaneus) was developed. When operating in transmission mode, the system can measure broadband ultrasonic attenuation-BUA, speed of sound--SOS and thickness of bone. BUA and SOS are measured by comparing the pulses transmitted through the heel with the reference pulse transmitted through water. In our approach, we operate in the backscattered mode in addition to transmission. The backscattered ultrasonic technique for bone characterization is very promising because the magnitude of backscattered waves depends on the scattering cross-section of a trabecular structure that, to some extent, describes the microarchitecture of a calcaneus. Additionally, when the backscattered and transmitted signals are compared, some of the signal distortions caused by tissue and bone interfaces are reduced. A set of data representing signals transmitted through the heel and reflected inside a calcaneus for patients with osteoporosis was collected. Several signal-processing techniques were applied in order to smooth the backscattered signal and to calculate a trabecular structure cros-section (TSC) function. Results obtained by these approaches along with a spectral shift method and a standard BUA measurement are presented and compared to X-ray bone mineral density determination results.

[Combined therapy with calcitonin and high doses of active vitamin D3 metabolites in uremic hyperparathyroidism]. / Skojarzone leczenie kalcytonina i duzymi dawkami aktywnych metabolitów witaminy D3 we wtórnej do mocznicy nadczynnosci przytarczyc.

Active vitamin D3 pulse therapy effectively suppresses parathormone (PTH) synthesis in uremic hyperparathyroidism but high serum levels of calcitriol achieved can induce direct osteoclastic resorption and block bone formation. Therefore we found it interesting to examine whether an addition of the osteoclast inhibitor, calcitonin (CT), could reduce those unwanted effects. 75 hemodialysis patients with at least 5-fold 1-84 PTH serum level elevation were divided into 4 treatment groups: I (n = 19)-CT and 1 alpha-OH-D3; II (n = 20)-CT; III (n = 19)-1 alpha-OH-D3 (n = 10) or 1.25 (OH)2D3 (n = 9) alone; IV (n = 17)-none of these drugs. CT (200 IU) and 1 alpha-OH-D3/1.25(OH)2D3 (up to 5 micrograms) were given 3 times a week. Dialysate Ca was 1.40-1.45 (Group I, III) or 1.95-2.00 mmol/l (Group II, IV). Within 8 months serum 1-84 PTH fell by 75% (p < 0.001) in Group I and by 77% (p < 0.001) in Group II, serum Ca increased by 0.22 +/- 0.05 mmol/l in Group I (p < 0.005) and by 0.25 +/- 0.05 mmol/l in Group III (p < 0.005), alkaline phosphatase activity decreased by 35% in Group I (p < 0.01) and 31% in Group III (p < 0.005) whereas in Groups II and IV no significant changes were noted. In Group III no differences between patients taking 1 alpha-OH-D3 or 1.25 (OH)2D3 were observed. The significant reduction of serum hydroxyproline (37%; p < 0.001) was seen only in Group 1. The increase in bone mineral density (BMD) measured by dual-energy X-ray absorptiometry was greater in Group I than in Group III (p < 0.05). In Group II the effect was mostly insignificant, whereas in Group IV a substantial decrease (p < 0.001) in BMD was observed. These data suggest that combined therapy with CT and oral 1 alpha-OH-D3 pulses is more effective than pulses alone in inhibiting bone resorption and in increasing BMD in hemodialysis patients with uremic hyperparathyroid bone disease.

Cultured parathyroid cells allotransplantation without immunosuppression for treatment of intractable hypoparathyroidism.

Cultured, viable and functioning ABO compatible parathyroid cells were allografted in 18 nonimmunosuppressed patients with a postoperative hypoparathyroidism. Variable, but promising biochemical and clinical results were obtained. Clinical and biochemical observations have documented graft function up to 14 months. The mechanism of cessation of function of implanted cultured cell suspension remains unknown. Some parameters, suggest a rejection mechanism but other mechanisms can not be excluded. This suggests that some form of immune modulation may be necessary to improve further PT allograft survival in recipients off immunosuppressive therapy.

[Allotransplantation of the parathyroid in patients without immunosuppression]. / Allotransplantacja przytarczyc u chorych bez immunosupresji.

Eighteen patients with postoperative insufficiency (after thyroid operations) have been treated with cultured, hormonally active, living and ABO the same group type parathyroid cells. Explants had been taken from 2 operated patients with secondary hyperparathyroidism. Hormonal activity of the transplanted parathyroid cells under the fascia of the brachio-radialis muscle has been confirmed by clinical, biochemical tests and the level of PTH in blood serum from the vein of non-grafted arm. Hormonal activity of the graft was variable but lasted up to 14 months.